The following background section is provided to aid in understanding the invention, but is not admitted to be or to describe prior art to the instant invention. All documents including patents, publications and patent applications referred to herein are hereby incorporated by reference in their entireties.
Macrolide compounds are known to be useful in treating and preventing a broad spectrum of bacterial and protozoal infections in mammals, fish and birds and are potential agents for the treatment of gastrointestinal motility disorders such as diabetic gastroparesis, non-ulcerative dyspepsia, irritable bowel syndrome and paralytic ileus in man.
These compounds, including derivatives of erythromycin A, are used and exhibit desirable activity against a number of Gram-positive pathogens. It is also well known that the widespread use of antibiotics over the past 70 years has resulted in the development of a host of antibiotic-resistant pathogens. Numerous examples of resistant infections have been documented in both the hospital and community settings. The present clinically used macrolide antibiotic compounds may be ineffective against these emerging resistant mutants. Therefore, it is of critical importance to develop and provide new drugs with broad-spectrum activity, particularly against drug-resistant strains.
Erythromycin A is a 14-membered macrolactone with good activity against many Gram-positive bacteria. Resistance to this class of antibiotics has been observed however, occurring by one of three mechanisms: (1) inactivation of the drug by chemical modification, (2) target modification such as ribosomal methylation (known as MLSB) or (3) by macrolide efflux. Furthermore Erythromycin A loses activity in acidic media and the decomposition products can give rise to gastric intolerance in many patients.
A second generation of macrolides, also natural products, contain a 16-membered ring e.g. spiramycin, first described in 1956 (G.B. Pat. No. 758,726). The 16-membered macrolides are also acid susceptible. Clarithromycin (U.S. Pat. No. 4,331,803) and azithromycin (U.S. Pat. No. 4,474,768) exemplify a third generation of macrolides. They are semi-synthetic derivatives of Erythromycin A, which overcome the problem of acid instability by preventing the formation of a 6,9-hemiketal by methylation of the 6-hydroxyl in the case of Clarithromycin and by the conversion of the 9-ketone to a tertiary amine in the case of Azithromycin.
Recently, a new class of macrolide compounds has been disclosed, namely, ketolides. Representative examples include telithromycin (U.S. Pat. No. 5,635,485) and ABT-773 (U.S. Pat. No. 6,028,181), which are designed particularly to combat respiratory tract pathogens that have acquired resistance to macrolides. The ketolides are semi-synthetic derivatives of the 14-membered macrolide erythromycin A. The preparation of these ketolides is disclosed in J. Med. Chem., 2000, 43, P. 1045. Current Microbiology, 2001, 42, P. 203. Bioorganic & Medicinal Chemistry Letters, 2000, 10, P. 2019. U.S. Pat. No. 6,420,535 and WO patent No. 99/21866. Ketolides are acid-stable and highly potent against most Gram-positive bacteria and do not induce MLSB resistance.
However, bacterial strains resistant to existing macrolides are being continually isolated and so there is an urgent need to identify new derivatives with improved activity against both Gram-positive and Gram-negative organisms and with superior resistance profiles.